Chemical synapses are connections between neurons in the human central nervous system that are fundamental to its development and normal function. At these points of nerve cell - nerve cell interaction, a chemical transmitter released from one cell diffuses across a small space, called the synapse, to receptors located on the opposing cell, triggering the opening of ligand-gated ion channels and the activation of other cell surface receptors. At excitatory synapses, the opening or activation of ligand-gated ion channels causes the influx of primarily sodium and calcium ions, depolarizing the cell and injecting a potent calcium signal. The activation and modulation of ligand- gated ion channels is thus a crucial component of signal transmission in the central nervous system. In this grant application, I propose to study the atomic structure of ionotropic glutamate receptors and acid sensing ion channels, two ubiquitous and important classes of ligand-gated ion channel. In the proposed experiments on essential fragments of the receptors, as well as on the intact receptors, I will define the precise atomic structure of these ligand-gated ion channels and will determine mechanisms of ion channel activation, inhibition and modulation. The proposed studies will reveal basic principles of ligand-gated ion channel function and they will also provide crucial molecular blueprints to guide the development of new pharmacological agents to treat debilitating diseases of the human nervous system. PUBLIC HEALTH RELEVANCE: Glutamate receptors and acid sensing ion channels are ligand-gated ion channel proteins that are essential to the normal development and function of the human nervous system and are integral to such fundamental processes as learning and memory. In this proposal we aim to determine their molecular structures and define principles for their activity, and thereby provide a foundation for development of new therapeutic agents to treat diseases of the human nervous system.